Toxicology and Management of SSRI Overdose - ce.mayo.edu · • ADE: Extravasation, alkalosis,...

©2018 MFMER | slide-1

Toxicology and Management of SSRI Overdose

Casey O’Connell, PharmD, RNPGY1 Pharmacy Practice Resident

October 9, [email protected]


“All things are poison, and nothing is without poison. The dosage alone makes it so a thing is not a poison.”–Paracelsus, founder of modern toxicology

Borzelleca JF. Paracelsus: herald of modern toxicology. Toxicol Sci. 2000 Jan;53(1):2-4.


Objectives1) Review potential toxicities associated with an acute SSRI overdose2) Identify pharmacological interventions used to treat patients who present with an acute SSRI overdose3) Review a patient case pertaining to the management of an acute SSRI overdose


Background• 11% of Americans use antidepressants• Antidepressant use has steadily increased• SSRIs most commonly prescribed antidepressant• >52,000 SSRI overdoses annually

• ~30,000 as polysubstance overdose• ~22,000 as single agent overdose

Pratt LA, et al. Antidepressant use in persons aged 12 and over: United States, 2005-2008. NCHS Data Brief. 2011 Oct(76):1-8.

Mowry JB, et al. 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol(Phila). 2016 Dec;54(10):924-1109.


SSRI Indications

FDA-ApprovedMajor depressive disorderGeneralized anxiety disorder Bipolar I disorder Bulimia nervosa Obsessive compulsive disorderSocial anxiety disorder Panic disorder Post-traumatic stress disorderPremenstrual dysphoric disorderVasomotor menopause symptoms

Antidepressants. Drug Facts and Comparisons. Facts & Comparisons eAnswers. Riverwoods, IL. Wolters Kluwer Health, Inc; May 2018. Accessed Sept 9, 2018.

Off-LabelBorderline personality disorderImpulsive aggressive behaviorBody dysmorphic disorderBinge eating disorder Raynaud phenomenonNeuropathic painFibromyalgiaTraumatic brain injurySelective mutismStuttering


Patient CaseCC: Altered mental status

HPI: 25 y.o. woman presenting 12 hours after ingesting an unknown quantity of fluoxetine and citalopram

PMH: Major depressive disorder, PTSD, migraine, UTI

Social: 1 PPD smoker

Family: Non-contributory

CC = Chief complaintHPI = History of present illnessPMH = Past medical history

PPD = Pack per dayPTSD = Post-traumatic stress disorderUTI = Urinary tract infection


Patient CaseMedication list:

• Ciprofloxacin 250 mg PO BID (UTI)

• Citalopram 20 mg PO daily (depression)*

• Quetiapine 300 mg PO daily (depression)

• Ondansetron 4 mg PO daily PRN (nausea)

• Sumatriptan 50 mg PO daily PRN (migraine)


Question 1Which medication from LK’s list has an overlapping toxicity with a fluoxetine and citalopram overdose?

A. CiprofloxacinB. OndansetronC. QuetiapineD. SumatriptanE. All of the above


Presynaptic Nerve Decreased reuptake:SSRIs, SNRIs, TCAs, bupropion, opioids

Postsynaptic NerveSerotonin

Serotonin Receptor

Serotonin agonism:Triptans, buspirone

Increased release:Cocaine, amphetamines, mirtazapine, buspirone

Decreased metabolism:MAOIs, linezolid,methylene blue

Upt

ake

Tran

spor

ter

Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013 Winter;13(4):533-40.


Toxicology of SSRI Overdose• Serotonin syndrome

• Altered mental status• Autonomic hyperactivity• Clonus

• Neurotoxicity• CNS depression• Seizure

• Cardiotoxicity• QT-interval prolongation• QRS widening

New AM, Nelson S, Leung JG. Psychiatric Emergencies in the Intensive Care Unit. AACN Adv Crit Care. 2015 Oct-Dec;26(4):285-93;


Patient CaseAfter triage our patient is agitated, flushed, febrile, and is noted to have ocular myoclonus. The consultant and senior resident are in the resuscitation bay when an intern approaches you for help.

The intern wants to know about differential diagnoses, monitoring, and medications that have been utilized in treating SSRI overdose.


Serotonin Syndrome

Neuroleptic Malignant Syndrome

Serotonergic drugs

Onset within 24 hours

Agitation

Hypertonia (especially in LE)

Hyperreflexia, clonus

Hyperactive bowel sounds, N/V, diarrhea

Hyperthermia

Hypertension

Tachycardia

Tachypnea

“stiff”

Dopamine antagonists

Onset days to weeks

Stupor, alert mutism

“Lead pipe” rigidity

Hyporeflexia

Hypoactive/normal bowel sounds


Hunter Criteria for Serotonin Syndrome• Serotonergic exposure and ≥1 of following:

• Spontaneous clonus• Hypertonia• Tremor AND hyperreflexia• Inducible clonus AND agitation OR diaphoresis• Ocular clonus AND agitation OR diaphoresis• Febrile >38°C AND ocular clonus OR

inducible clonus

Dunkley EJC, et al. The Hunter Serotonin Toxicity Criteria: Simple and accurate diagnostic decision rules for Serotonin Toxicity. Q J Med 2003;96:635-642.


SSRI Overdose Monitoring• Vitals

• Core temp• HR• BP• RR• SPO2

• Cardiac monitoring• Baseline 12-lead ECG• Continuous monitor• QTc monitoring

• Strict I/O

• Labs• Co-ingested drugs• CK• CMP• CBC• PT/INR• aPTT• ABG• Urinalysis

• Lumbar puncture• Head CT

Sporer KA, Khayam-Bashi H. Acetaminophen and salicylate serum levels in patients with suicidal ingestion or altered

Hurlbut, KM. Neuroleptic Malignant Syndrome and Serotonin Syndrome. The 5 Minute toxicology Consult. Philadelphia, PA: Lippincott Williams and Wilkins 2000; p 54


Serotonin Syndrome Management

Removal of serotonergic agents

Benzodiazepine administration

Consider gastric decontamination

Consider paralysis and intubation

Consider cyproheptadine


Cyproheptadine in Serotonin Syndrome• 5-HT2 antagonism at high doses• PO/NGT route only• 12 mg followed by 2 mg Q2H initially• 4-8 mg Q6H for maintenance• Only consider in moderate-severe cases• ADE: Sedation, confusion, hypotension,

palpitations, tachycardia

Boyer EW, Shannon M. The Serotonin Syndrome. New England Journal of Medicine. 2005;352:1112-20.

Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol. 1999;13(1):100-9.


Presynaptic Nerve

Postsynaptic NerveSerotonin

Serotonin Receptors

Upt

ake

Tran

spor

ter

Cyproheptadine

SSRI



Serotonin Syndrome Management• Kapur, et al in vivo study

• Basis of cyproheptadine use in serotonin syndrome

• Included 2 healthy adult volunteers

• Cyproheptadine 4 mg vs 6 mg TID for 6 days

• Evaluated 5-HT2 receptor occupation

• Results:• 85% receptor blocking in 4 mg TID subject• >95% receptor blocking in 6 mg TID subject

Kapur S, et al. Cyproheptadine: a potent in vivo serotonin antagonist. Am J Psychiatry. 1997 Jun;154(6):884. Evaluated 5-HT2 receptors before and 4 hours after cyproheptadine administration


Patient CaseUsing Hunter’s Criteria the intern diagnoses our patient with serotonin syndrome and enters orders to obtain a 12-lead ECG, draw labs, initiate parenteral fluids, and place the patient on 1-to-1 observation for suicidality.

Minutes later the patient has a tonic-clonic seizure.


Question 2What would you choose as your initial treatment option for this patient’s seizures?

A. FosphenytoinB. LevetiracetamC. LorazepamD. Phenobarbital E. Valproic acid


Neurotoxicity in SSRI Overdose

• CNS depression• Extension of pharmacological activity

• Seizures• Early finding in overdose• Most common in citalopram, escitalopram• Dose-related risk increase• Typically noted in concentrations 40x

therapeutic levels



Neurotoxicity in SSRI Overdose

• Initial seizure management• Lorazepam 2-8 mg IV q 10-15 min PRN• Diazepam 5-10 mg IV q 5-10 min PRN

• Refractory seizure management• Phenobarbital 10-20 mg/kg IV• Propofol 0.5-2 mg/kg IV bolus followed by

20 mcg/kg/min IV infusion and titrated• Neuromuscular blockade and intubation



Pathway for Rhabodomyolysis


Myoclonus

Hyperthermia

Seizure

Rhabdomyolysis


Patient CaseAfter the seizure our patient is intubated and admitted to MICU. Later that day a repeat ECG is ordered and the following results are noted:

Rate 96QRS 90QTc 541


Question 3What medication will you administer if our patient develops torsades de pointes? (Rate 96, QRS 90, QTc 541)

A. AmiodaroneB. Calcium chloride C. Magnesium sulfate D. MetoprololE. Sodium bicarbonate


Cardiotoxicity in SSRI Overdose

• QT interval prolongation • QTc >500 msec associated with

torsades de pointes• Elevated risk with baseline prolonged

QT and co-ingestion • Delayed effect ~24 hours• Observed with citalopram and

escitalopram ingestion

Catalano G, et al. QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol. 2001 May-Jun;24(3):158-62.

Yuksel FV, Tuzer V, Goka E. Escitalopram intoxication. EurPsychiatry. 2005 Jan;20(1):82.

Link MS, et al. Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015 Nov 3;132: S444-64.



• Treatment of torsades• Magnesium sulfate 1-2 grams IV over 15 min• Non-cardiac arrest: infuse in 100 mL D5W• Cardiac arrest: dilute in 10 mL and push IV• Baseline magnesium level not required• ADE: Hypotension, CNS depression, flushing

Link MS, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015 Nov 3;132(18 Suppl 2): S444-64.


Na+SSRIBicarbonate

Mechanism of QRS Widening


Cardiotoxicity: QRS widening in SSRI Overdose

• Observed with massive ingestions• Sodium bicarbonate 1-2 mEq/kg bolus

• Bolus until narrowing observed• Follow with maintenance infusion 150 mEq/L• Sodium load and elevated pH displace drug

from sodium channels• ADE: Extravasation, alkalosis, hypernatremia,

edema, heart failure exacerbation

Graudins A, Vossler C, Wang R. Fluoxetine-induced cardiotoxicity with response to bicarbonate therapy. Am J Emerg Med. 1997 Sep;15(5):501-3.

Brucculeri M, Kaplan J, Lande L. Reversal of citalopram-induced junctional bradycardia with intravenous sodium bicarbonate. Pharmacotherapy. 2005 Jan;25(1):119-22.


Intravenous Lipids in SSRI Overdose• First utilized in overdose in 1962• Creates an intravascular “lipid sink”• Historically used in anesthetic toxicity• Use expanding to other lipophilic drugs• ADEs: Thrombophlebitis, pulmonary infiltration,

cholestasis, pancreatitis, infusion reaction

Eren-Cevik S, et al. Intralipid emulsion treatment as an antidote in lipophilic drug intoxications. Am J Emerg Med. 2014 Sep;32(9):1103-8.


Intravenous Lipids in SSRI Overdose

Eren-Cevik, et al

• Case series of 10 adult overdoses receiving intravenous lipids

• 7 antidepressants, 2 SSRIs

• Both SSRI overdoses polypharmacy

• 9 of 10 patients survived overdose

• Improvements in GCS, HR, and BP

• 2 patients developed ADE• Hyperamylasemia• Lung infiltration• Urine color change

Purg, et al

• Single adult polypharmacy overdose

• ≥400 mg citalopram

• Refractory status epilepticus

• QTc 570 msec, VT

• No ADE noted

• After infusing lipids• Resolution of seizures• Resolution of VT• Extubated 24 hours later

Purg D, et al. Low-dose intravenous lipid emulsion for the treatment of severe quetiapine and citalopram poisoning. Arh HigRada Toksikol. 2016 Jun 1;67(2):164-6.

Eren-Cevik S, et al. Intralipid emulsion treatment as an antidote in lipophilic drug intoxications. Am J Emerg Med. 2014 Sep;32(9):1103-8.


Safety of SSRIs in Overdose• Safer than TCA and MAOI in overdose• Minimal interaction with other targets• 15% develop serotonin syndrome • 5% require mechanical intubation• 2% develop seizures


Beaune S, et al. Do serotonin reuptake inhibitors worsen outcome of patients referred to the emergency department for deliberate multi-drug exposure? Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):372-7.


Safety of SSRIs in Overdose• Beaune, et al

• Retrospective chart review of deliberate multi-drug overdoses

• 148 exposed patients vs 296 controls• Serotonin syndrome underdiagnosed • No difference in arrhythmia (p=0.1)• Exposed had increased seizures (p=0.04) • Exposed had increased intubation (p=0.03)

Beaune S, et al. Do serotonin reuptake inhibitors worsen outcome of patients referred to the emergency department for deliberate multi-drug exposure? Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):372-7.


SSRI Overdose Summary• Manage by stopping serotonergic agents, giving

benzodiazepines, and supportive care

• Treat seizures with high dose benzodiazepines

• Manage ECG changes with intravenous magnesium and sodium bicarbonate

• Minimal evidence supporting cyproheptadine use for serotonin syndrome

• No evidence to support intravenous lipids outside of polysubstance overdose


Patient Case ResolutionOn hospital day 2 our patient is no longer showing signs of serotonin syndrome and is extubated without incident.

Later that day a repeat ECG demonstrates a QTc of 475 and our patient is subsequently discharged to the inpatient psychiatric unit. While recovering, a note is placed in her chart to avoid all serotonergic agents for several weeks.


Toxicology and Management of SSRI OverdoseCasey O’Connell, RN, PharmDPGY1 Pharmacy Practice Resident

October 9, [email protected]


DefinitionsPharmacology: the study of drugs including their origin, composition, pharmacokinetics, and therapeutic use

Toxicology: the study of poisons, their detection, effects, and the methods of treatment for conditions they produce

Toxidrome: a specific constellation of symptoms associated with exposure to a given poison

Mosby's Medical Dictionary, 9th edition. © 2009, Elsevier

SDN5

SDN5 I'll be interest to see how you plan to transition into and out of this slide. I see what your doing by adding it, but I might ask you if it is necessary or if these points can be verbalized when they come up in your presentation. It's all a flow thing, so both could be correctand once you describe in person your flow it will be more clear. Scott D Nei, 9/19/2018



• QRS widening • QRS >100 msec• Rare in SSRI overdose• Bind and alter sodium channel conformation• Altered channels impair myocardial conduction

• Negative dromotropic• Negative inotropic

Graudins A, Vossler C, Wang R. Fluoxetine-induced cardiotoxicity with response to bicarbonate therapy. Am J Emerg Med. 1997 Sep;15(5):501-3.

Brucculeri M, Kaplan J, Lande L. Reversal of citalopram-induced junctional bradycardia with intravenous sodium bicarbonate. Pharmacotherapy. 2005 Jan;25(1):119-22.


Miscellaneous SSRI Pearls and Toxicities• Sertraline is most widely prescribed

• Citalopram and paroxetine most anticholinergic, sedating

• Paroxetine and fluvoxamine have no active metabolites

• Paroxetine highly associated with discontinuation syndrome

• Fluoxetine’s half-life precludes restarting antidepressants

• All SSRIs may inhibit platelet aggregation

• All SSRIs associated with SIADH


Background• Selective serotonin reuptake inhibitors (SSRIs) are

first line therapy for depression and anxiety

• Marketed in 1980’s for treatment of depression

• Use expanded to other neuro/psych disorders

• Safer than MAOI and TCA antidepressants

• Boxed warning for suicidality

Moore TJ, Mattison DR. Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. JAMA Intern Med. 2017 Feb 1;177(2):274-275.

Mowry JB, et al. 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol (Phila). 2016 Dec;54(10):924-1109.


SSRI Overdose Epidemiology• 12% of American adults take antidepressants

• 4 of 5 take antidepressants long-term

• Antidepressant use increases with age

• Highest use in Whites, lowest in Asians

• 2:1 female to male ratio

• >52,000 SSRI overdoses annually

• >22,000 overdosed on SSRI alone

• Serotonin syndrome in ~15% of SSRI overdoses

Mowry JB, et al. 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol (Phila). 2016 Dec;54(10):924-1109.

Moore TJ, Mattison DR. Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. JAMA Intern Med. 2017 Feb 1;177(2):274-275.

Boyer EW, Shannon M. The Serotonin Syndrome. New England Journal of Medicine. 2005;352:1112-20.


Slide adapted from content by Maria Rudis and used with permission


Mechanisms to Increase Serotonin• Enhancing serotonin release• Blocking serotonin reuptake• Inhibiting serotonin metabolism• Serotonin receptor agonism

Stork, CM. Serotonin Reuptake Inhibitors and Atypical Antidepressants. Goldfrank’s Toxicologic Emergencies 9th Edition. Stanford: Appleton and Lange 2011; 1037-1048.


Serotonin Syndrome vs Neuroleptic Malignant Syndrome

Serotonin Syndrome NMSExposure Serotonergic drugs Dopamine antagonistsOnset Within 24 hours Days to weeksVitals Hyperthermia, hypertension,

tachycardia, tachypnea Hyperthermia, hypertension,tachycardia, tachypnea

Mentation Agitation, coma Stupor, alert mutism, comaSkin Diaphoresis Diaphoresis, pallorMuscles Hypertonia (especially in LE) “Lead pipe” rigidityReflexes Hyperreflexia, clonus HyporeflexiaPupils Mydriasis NormalBowels Hyperactive, N/V, diarrhea Normal/hypoactiveRecovery Usually within 24 hours Up to 10 days

New AM, Nelson S, Leung JG. Psychiatric Emergencies in the Intensive Care Unit. AACN Adv Crit Care. 2015 Oct-Dec;26(4):285-93;

Nisijima K. Serotonin syndrome overlapping with neuroleptic malignant syndrome: A case report and approaches for differentially diagnosing the two syndromes. Asian J Psychiatr. 2015 Dec;18:100-1.


Serotonergic Agents

Antidepressants Drugs of abuse AntiemeticsSSRIs Amphetamines GranisetronSNRIs Cocaine OndansetronTCAs MDMA MetoclopramideMAOIs LSD TriptansBuproprion Herbals/Supplements MiscellaneousTrazodone St. John’s Wort DextromethorphanAnalgesics Ginseng CarbamazepineCodeine Tryptophan Methylene blueTramadol Dopamine Agonists BuspironeMethadone Levodopa LithiumFentanyl Bromocriptine LinezolidMeperidine Amantadine Mirtazapine


Toxicology and Management of SSRI Overdose - ce.mayo.edu · • ADE: Extravasation, alkalosis,...

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